Cases Of Nonimmune Hydrops Fetalis Research Articles

RASopathies are the most common set of monogenic syndromes identified by exome sequencing for nonimmune hydrops fetalis: A systematic review and meta-analysis.

RASopathies are a group of malformation syndromes known to lead to nonimmune hydrops fetalis (NIHF) in severe presentations. Pathogenic variants can be de novo or parentally inherited. Despite being a known frequent presentation, the fraction of monogenic NIHF cases due to RASopathies is limited in the literature. Also, the specific parental contribution of RASopathies to NIHF is not well described. Our objective was to review pooled exome sequencing (ES) diagnostic yield of RASopathies for NIHF and to determine the parental contribution of RASopathy to NIHF. We performed a systematic review of prenatal ES studies from January 1, 2000 to August 1, 2022. Thirty-six studies met inclusion criteria. Cases with RASopathy gene variants were reviewed. NIHF cases were further classified as isolated or non-isolated. Thirty-six ES studies including 46 pregnancies with NIHF and a diagnosed RASopathy were reviewed. Forty-four diagnostic variants and 2 variants of uncertain significance in 12 RASopathy genes were identified. Expanding on what was previously published, a total of 506 NIHF cases were extracted with 191 cases yielding a positive diagnosis by ES. The overall rate of RASopathy diagnosis in clinically diagnosed NIHF cases was 9% (44/506). The rate of RASopathy diagnosis among NIHF cases with positive genetic diagnosis by ES was 23% (44/191). Of the 46 cases identified, 13 (28%) variants were parentally inherited; specifically, 5/13 (38%) maternal, 3/13 (23%) paternal, 2/13 (15%) biparental, and 3/13 (23%) unspecified. Majority of NIHF cases 29/46 (63%) were isolated. Among NIHF cases with positive ES diagnoses, RASopathy diagnostic yield by ES was 23%. NIHF secondary to RASopathies was parentally inherited in 28% of cases. Most cases of NIHF due to RASopathy were isolated, with no prenatal detection of associated anomalies.

The Course, Prognosis, and Hand-Holding of Parents in Nonimmune Hydrops Fetalis—A Case Report with a Brief Review

AbstractHydrops fetalis (HF) is a serious fetal condition characterized by abnormal accumulation of fluid in fetal soft tissues and serous cavities. HF can be immune hydrops fetalis (IHF) or nonimmune hydrops fetalis (NIHF) depending upon the presence of antibodies in the mother. We report a case of euploid NIHF who delivered at 34 weeks and had spontaneous recovery. The baby had gross fetal ascites and mild pleural and pericardial effusion. After a thorough workup, no definite cause could be found. However, the ascites spontaneously resolved. The baby had many peaks and valleys during the initial 3 months of life, doing well at 6 months of age and is under follow-up. This case report highlights the practical workup and diagnostic algorithm of NIHF and provides an updated review.

Diagnostic yield from prenatal exome sequencing for non-immune hydrops fetalis: A systematic review and meta-analysis.

Non-immune hydrops fetalis (NIHF) has multiple genetic etiologies diagnosable by exome sequencing (ES). We evaluated the yield of prenatal ES for NIHF, and the contribution of additional clinical findings and history. Systematic review was performed with PROSPERO tag 232951 using CINAHL, PubMed, and Ovid MEDLINE from January 1, 2000 through December 1, 2021. Selected studies performed ES to augment standard prenatal diagnostic approaches. Cases meeting a strict NIHF phenotype were tabulated with structured data imputed from papers or requested from authors. Genetic variants and diagnostic outcomes were harmonized across studies using current ACMG and ClinGen variant classification guidelines. Thirty-one studies reporting 445 NIHF cases had a 37% (95% CI: 32%-41%) diagnostic rate. There was no significant difference between isolated NIHF and NIHF with fetal malformations or between recurrent and simplex cases. Diagnostic rate was higher for consanguineous than non-consanguineous cases. Disease categories included RASopathies (24%), neuromuscular (21%), metabolic (17%), lymphatic (13%), other syndromes (9%), cardiovascular (5%), hematologic (2%), skeletal (2%), and other categories (7%). Inheritance patterns included recessive (55%), dominant (41%), and X-linked (4%). ES should be considered in the diagnostic workup of NIHF with and without associated ultrasound findings regardless of history of recurrence or consanguinity.

A Retrospective Analysis of Cases of Non-Immune Hydrops Fetalis in A Tertiary Center

A Retrospective Analysis of Cases of Non-Immune Hydrops Fetalis in A Tertiary Center

An Investigation of the Etiologies of Non-Immune Hydrops Fetalis in the Era of Next-Generation Sequence-A Single Center Experience.

(1) Background: Numerous etiologies may lead to non-immune hydrops fetalis (NIHF). However, the causes remain unclear in half of NIHF cases following current standard assessment. The application of prenatal chromosomal microarray analysis (CMA) and exome sequencing (ES) can improve the identification of the etiologies. This study aimed to investigate the etiologies of NIHF in the era of next-generation sequence (NGS) following a unified prenatal work-up flow for diagnosis. (2) Methods: A retrospective analysis was conducted on NIHF cases that were collected prospectively to explore the underlying etiologies according to a unified prenatal diagnosis work-up flow at Shanghai First Maternity and Infant Hospital between Jan 2016 and Dec 2019. The medical records for all NIHF cases were reviewed, and the causes of NIHF were classified as confirmed (diagnostic), suspected, or unknown. (3) Results: Prenatal and postnatal medical records for a total of 145 NIHF cases were reviewed, 48.3% (70/145) of the cases were identified to be with confirmed etiologies, and 10.3% (15/145) with suspected etiologies. Among 85 cases with confirmed or suspected etiologies, 44.7% were diagnosed with genetic disorders, 20% with chylothorax/chyloascites diagnosed postnatally, 12.9% with fetal structural anomalies, 12.9% with fetal anemia, 7% (6 cases) with fetal arrhythmia, and 2.3% (2 cases) with placenta chorioangioma. In cases with genetic disorders, 8 aneuploidies were detected by CMA, and 30 cases had single-gene disorders identified by ES (29/30) or targeted gene panel (1/30). There were still 41.4% cases (60/145) with unknown causes after this unified prenatal diagnostic work-up flow. (4) Conclusions: In the era of NGS, the causes of NIHF were identified in 58.6% of cases, with genetic disorders being the most common ones. NGS is helpful in determining the genetic etiology of NIHF when CMA results cannot explain NIHF, but 41.4% of cases were still with unknown causes under the unified prenatal diagnostic work-up flow in this single-center study.

Galactosialidosis presenting as non-immune hydrops in a newborn: A case report

Galactosialidosis is a rare autosomal recessive lysosomal storage disorder (LSD). It results from defects in glycoprotein degradation due to mutation in a single gene, encoded by the protective protein cathepsin A, (CTSA), located on chromosome 20q13.12. Most cases of non-immune hydrops fetalis (NIHF) nowadays being recognized are due to cardiac, lymphatic dysplasia, and hematological disorders. Inborn errors of metabolism account for NIHF in 1.3% of patients. Among metabolic disorders, around 14 LSDs have been reported as being associated with NIHF and congenital ascites. In the present case, we report an early infantile form of galactosialidosis with a novel homozygous miss-sense mutation c.319 A>C (p. Ser107 Arg) in exon 3 of CTSA gene in a newborn who presented as non-immune hydrops. The baby also had coarse facies, wide anterior fontanelle, hypertelorism, bilateral congenital talipes equinovarus, hepatosplenomegaly, nephrocalcinosis, and disproportionately small limbs with metaphyseal irregularity. Gradually, he developed worsening cardiac functions and cardiomyopathy and succumbed to death on day 47 of life. Being an autosomal recessive disorder, it can recur in the next pregnancy and treatment is mainly supportive. Targeted prenatal diagnostics in subsequent pregnancies can help in early diagnosis.

Isolated non-immune hydrops fetalis: an observational study on complete spontaneous resolution, perinatal outcome, and long-term follow-up

PurposeThe aim of our study was to investigate spontaneous resolution and postnatal outcome in non-immune hydrops fetalis (NIHF). We specifically studied NIHF cases that occurred without any other anomalies in the prenatal diagnostic workup, defined as isolated NIHF (iNIHF).MethodsTo identify iNIHF we retrospectively classified prenatal findings of 700 NIHF singletons, diagnosed in our prenatal referral center between 1997 and 2016. We studied the occurrence of prenatal resolution in iNIHF and linked it to the perinatal outcome. We obtained long-term outcome by contacting the parents, children, and the pediatricians and listed all functional and structural anomalies and temporary logopedic, psychosocial and motoric impairments.ResultsAmong 70 iNIHF cases, 54 (77.1%) resolved completely prenatally. The baby-take-home rate was 98.1% in these cases. In contrast, the baby-take-home rate in the subgroup without complete resolution was 25.0%.We achieved pediatric long-term outcome in 27 of 57 survivors (47.4%) of iNIHF with a mean follow-up period of 10.9 years. Among these 27 children, fetal hydrops had completely resolved prenatally in 26 cases and had regressed to a mild effusion in one case. In the pediatric development, two children had significant functional impairment and two children showed recurrent skin edema.ConclusionComplete spontaneous resolution was the most common intrauterine course of iNIHF in our collective. Completely resolved iNIHF had a favorable perinatal outcome in our study. Our data on the long-term outcomes are consistent with the assumption of an increased rate of functional impairments.Trial registryInternal study number of Heinrich-Heine-University, Duesseldorf: 6177R. Date of registration: December 2017.

Cost-Effectiveness of Exome Sequencing versus Targeted Gene Panels for Prenatal Diagnosis of Fetal Effusions and Non-Immune Hydrops Fetalis

Although exome sequencing has a greater overall diagnostic yield than targeted gene panels in the evaluation of nonimmune hydrops fetalis and fetal effusions, the cost-effectiveness of this approach is not known. This study aimed to evaluate the costs and outcomes of targeted gene panels vs exome sequencing for prenatally diagnosed nonimmune hydrops fetalis and fetal effusions when next-generation sequencing is pursued following nondiagnostic standard nonimmune hydrops fetalis evaluations, including karyotype or chromosomal microarray. A decision-analytical model was designed using TreeAge Pro to compare 10 genetic testing strategies, including a single test only (RASopathy, metabolic, or nonimmune hydrops fetalis-targeted gene panel or exome sequencing), sequential testing (RASopathy panel followed by nonimmune hydrops fetalis panel, metabolic panel followed by nonimmune hydrops fetalis panel, RASopathy panel followed by exome sequencing, metabolic panel followed by exome sequencing, and nonimmune hydrops fetalis panel followed by exome sequencing), and no additional genetic testing. Our theoretical cohort included cases with normal karyotype and/or microarray and excluded cases of alloimmunization and congenital viral infections. As nonimmune hydrops fetalis and fetal effusions can present throughout gestation, whereas pregnancy management options vary depending on gestational age, outcomes were calculated for 3 time intervals: 10 to 18, 18 to 22, and >22 weeks of gestation. The primary outcome was incremental cost per quality-adjusted life year. Additional outcomes included termination of pregnancy, stillbirth, neonatal death, and neonates born with mild, moderate, and severe or profound disease phenotypes. The cost-effectiveness threshold was $100,000 per quality-adjusted life year. Among women <18 weeks of gestation, exome sequencing alone was the dominant strategy associated with the lowest costs ($221 million) and the highest quality-adjusted life years (10,288). Strategies with exome sequencing alone or as a sequential test resulted in more terminations but fewer stillbirths, neonatal deaths (NNDs), and affected infants than strategies without exome sequencing. Among women between 18 and 22 weeks of gestation, exome sequencing alone was also associated with the lowest costs ($188 million) and the highest quality-adjusted life years (8734), and similar trends were observed in pregnancy outcomes. Among patients >22 weeks of gestations, when termination was not available, exome sequencing was associated with lower costs ($300 million) and the highest quality-adjusted life years (8492). Exome sequencing was cost-effective up to a cost per test of $50,451 at <18 weeks of gestation, $50,423 at 18 to 22 weeks of gestation, and $9530 at >22 weeks of gestation. Targeted genetic panels and exome sequencing were cost-effective strategies compared with no additional genetic testing. For cases of nonimmune hydrops fetalis and fetal effusions with nondiagnostic karyotype or microarray, next-generation sequencing was cost-effective compared with a strategy without additional genetic testing. For those that undergo next-generation sequencing, exome sequencing was the cost-effective strategy compared with all other testing strategies using targeted gene panels, leading to lower costs and fewer adverse perinatal outcomes. Exome sequencing was cost-effective in a setting without the option for pregnancy termination. These data supported the routine use of exome sequencing when next-generation sequencing is pursued for establishing a genetic diagnosis underlying otherwise unexplained nonimmune hydrops fetalis and fetal effusions.

A single center experience in 90 cases with nonimmune hydrops fetalis: diagnostic categories ‒ mostly aneuploidy and still often idiopathic

The prognosis of nonimmune hydrops fetalis (NIHF) is still poor with a high mortality and morbidity rate despite progress in perinatal care. This study was designed to investigate etiology and outcome of NIHF. A retrospective review of 90 NIHF cases from 2007 to 2019 was conducted at University Medical Center of the Johannes Gutenberg University, Mainz, Germany. Demographics, genetic results, prenatal and postnatal outcomes including one year survival as well as autopsy data were extracted. Etiology of hydrops was classified using 13 previously established categories. In 4 patients observed between 2016 and 2019, we used a next-generation-sequencing (NGS) panel for genetic evaluation. Ninety NIHF cases were identified, with a median gestational age (GA) at diagnosis of 14weeks. There were 25 live-born infants with a median GA of 34weeks at birth, 15 patients survived to one year. There was aneuploidy in more than one third of the cases. All 90 cases were subclassified into etiologic categories with chromosomal 35, idiopathic 15, syndromic 11, cardiovascular 9, inborn errors of metabolism 6, lymphatic dysplasia 3, thoracic 3, infections 3, gastrointestinal 3 and hematologic 2. The NGS panel was used in 4 cases and 4 diagnoses were made. In 90 cases with NIHF we identified an aneuploidy in more than one third of the cases. Improved techniques, such as possibly specific genetic analysis, could reduce the high rate of unexplained cases of NIHF.

A Nonimmune Hydrops Case.

A Nonimmune Hydrops Case.

OP051: Genetic characteristics and prenatal phenotyping of RASopathy spectrum diagnosed by exome sequencing for nonimmune hydrops fetalis

RASopathies are a large group of malformation syndromes caused by variants in genes encoding the Ras/mitogen-activated protein kinase signaling pathway. RASopathies are known to frequently cause nonimmune hydrops fetalis (NIHF). The contribution of parental inheritance of RASopathy causing NIHF is limited. Our objective was to review the genetic characteristics and prenatal phenotype of NIHF cases due to RASopathy.

The Value of Exome Sequencing in Thoracoamniotic Shunt for Severe Pleural Effusion with Fetal Hydrops: A Retrospective Clinical Study

Objective: We aimed to study the value of exome sequencing (ES) in severe pleural effusion with nonimmune hydrops fetalis (NIHF) that underwent thoracoamniotic shunt (TAS). Methods: It was a retrospective study of NIHF that underwent TAS between 2012 and 2020 at Shanghai First Maternity and Infant Hospital. After a detailed assessment, NIHF cases with aneuploidies, infections, and structural anomalies were excluded, and TAS was offered to cases with severe pleural effusion. Quantitative fluorescence polymerase chain reaction (QF-PCR) was conducted to exclude Trisomy 21, 18, and 13 before fetal therapy, and chromosomal microarray analysis (CMA) was offered to all the cases. Before 2019, ES was retrospectively performed using stored fetal DNA extracted from prenatal samples; from 2019 onward, ES was discussed and offered before intrauterine therapies. Results: A total of 18 NIHF cases underwent TAS with negative CMA and continuing pregnancy were included. Fetal hydrops was relieved in 16 cases (88.9%). The median gestational ages at intervention and at delivery were 31.2 (22.0–33.1) weeks and 34.3 (29.7–38.6) weeks, respectively. The neonatal survival rate was 72.2% (13/18), and no causative gene variants were identified from ES in any survivors. Pathogenic or likely pathogenic variants were detected in 3 out of 5 neonatal deaths. If rapid ES could have been available to guide fetal therapy, the neonatal survival rate after TAS would have increased from 72.2% to 86.7%. Conclusions: Single-gene disorders were one of the major causes of perinatal death in NIHF cases that underwent fetal therapy. Prenatal rapid ES may be of good promise in NIHF to explore precise etiology and guide fetal therapy.

Perinatal Outcomes of 91 Cases of Non-Immune Hydrops Fetalis

Perinatal Outcomes of 91 Cases of Non-Immune Hydrops Fetalis

Fetal hydrops and the Incremental yield of Next‐generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta‐analysis

To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non-immune hydrops fetalis (NIHF). A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound-based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected). In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non-isolated NIHF. In the meta-analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24-34%; P < 0.00001; I2 = 0%) in all NIHF, 21% (95% CI, 13-30%; P < 0.00001; I2 = 0%) in isolated NIHF and 39% (95% CI, 30-49%; P < 0.00001; I2 = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51). Use of prenatal next-generation sequencing in both isolated and non-isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole-genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Non-immune fetal hydrops in late pregnancу: antenatal ultrasound monitoring and pregnancy outcomes in a series of 14 cases

Background. Fetal hydrops is the accumulation of extracellular fluid in two or more fetal cavities, often in combination with subcutaneous edema. An isolated accumulation of fluid only in the abdominal, pleural, or pericardial cavities is described as ascites, pleural effusion (hydrothorax), pericardial effusion (hydropericardium). Features of the pathogenesis of non-immune hydrops fetalis (NIHF) are the follow: high hydrophilicity of fetal tissues, obstruction of the lymphatic vessels, impaired lymph return, congestive heart failure, obstruction of venous return, changes in fetal venous pressure. All these factors lead to the release of fluid from cells and tissues into the «third» spaces – the abdominal, thoracic, pericardial cavities, as well as the subcutaneous space. The oncotic pressure of fetal plasma proteins is not of great importance in the formation of the fetal circulating blood volume. Currently, all the links in the pathogenesis of hydrops fetalis syndrome with various etiological factors are not fully known. The prevalence of NIHF is unknown because it is difficult to collect relevant data; many cases of the disease are not diagnosed until intrauterine fetal death or may spontaneously resolve during the prenatal period. Currently, up to 90% of all cases of fetal dropsy are attributed to NIHF. Purpose – acquaintance of the medical community with the diagnosis and treatment of non-immune hydrops as well as the analysis of clinical features, ultrasound monitoring and perinatal outcomes of 14 cases of non-immune fetal hydrops onset in a second half of pregnancy. Materials and methods. The material for the study were publications and results of clinical trials found in the databases Scopus, Web of Science Core Collection and PubMed for the period 2009–2020 and the analytic report of the own series of 14 cases of non-immune hydrops fetalis (NIHF) of various origins. During the period of 2005–2020 under the supervision in the Ultrasound Department of Kharkiv regional hospital with regional perinatal center there were 14 pregnant women with NIHF diagnosed in a second half of pregnancy. Clinical features are described, ultrasound images and Doppler monitoring are given, perinatal / postnatal results are studied. Results and discussion. The analysis of clinical features, ultrasound monitoring and pregnancy outcomes of 14 cases of non-immune fetal hydrops developed in the second half of pregnancy in presented series was carried out. 6/14 fetuses had structural anatomical defects (lung sequestration, СDH, myasthenia gravis, megacystis and hydronephrosis, epidermolysis bullosa, meconium peritonitis, intestinal atresia). Mortality rate (including perinatal and infant losses) was as high as 9/14 cases (64.2%): 3 of antenatal, 4 of neonatal, 2 of infant death). Surgical treatment was performed on 2 newborns. 5 newborns had apparently a favorable clinical postnatal outcome. In 2 cases, spontaneous resolution with complete regression of hydrops was observed (parvovirus-B19 and idiopathic NIHF). Complete recovery of fetus (spontaneous regression of hydrops without any deterioration and pathological consequences) was observed in 1 case. Conclusions. Antenatal ultrasound monitoring of fetus with NIHF is based on the assessment of PSV CMA, ductus venous, umbilical vein, atrioventricular flow. According to the results of the study, it was revealed that the cardiovascular profile of the fetus with NIHF is disturbed earlier, and the placental profile and arterial Doppler-later. Normal umbilical artery Doppler do not exclude the possibility of an adverse outcome, including intrauterine fetal demise. Extended Doppler monitoring is essential at NIHF. All neonates with NIHF in an antenatal anamnesis require postnatal follow-up.

Etiology and outcome of non-immune hydrops fetalis in relation to gestational age at diagnosis and intrauterine treatment.

To determine the etiology and outcome of non-immune hydrops fetalis (NIHF) according to gestational age at diagnosis and intrauterine treatment. A total of 122 NIHF cases were included. Medical records and ultrasonographic images were reviewed. The etiology, outcome, and intrauterine treatment were assessed. The etiology was determined in 100 cases, and Hb Bart's disease was the most common. Two cases each of homozygous Southeast Asian ovalocytosis (SAO) and hemoglobin Constant Spring (Hb CS) were found. NIHF diagnosed in early gestation (<24 weeks) had a higher rate of chromosomal abnormalities and fetal demise. Intrauterine treatment was given in 18 cases, and 50% had successful live births. Hb Bart's disease was the most common cause of NIHF. SAO and Hb CS were associated with hydrops. NIHF in gestational age <24 weeks was associated with chromosomal abnormalities and fetal demise. Intrauterine treatment should be offered in selected cases.

Lysosomal storage disorders as an etiology of nonimmune hydrops fetalis: A systematic review

We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSD) in case series of nonimmune hydrops fetalis (NIHF). PubMed and Ovid were reviewed for case series evaluating the workup of NIHF diagnosed in utero or in the neonatal period in human subjects from 1979 to August 2020. Retrospective case series with at least five cases of fetal and/or neonatal NIHF with its workup mentioned were identified. Idiopathic NIHF was defined as NIHF without an apparent cause after initial standard-of-care workup. In total, twenty-two case series with 2,678 total cases of NIHF were identified. The overall incidence of LSD was 6.6% (177/2,663) in NIHF cases that were tested for any LSD, and 8.2% (177/2,151) in idiopathic NIHF cases. The most common LSD identified in cases of NIHF were mucopolysaccharidosis type VII, galactosialidosis, infantile sialic acid storage disease, Gaucher disease, GM1 gangliosidosis and sialidosis. More than 40% of the most common LSD causes of NIHF have a potential postnatal treatment. LSD testing for NIHF allows for early diagnosis, better counseling and appropriate management, planning for possible early treatment, and counseling for recurrence risk.

The many etiologies of nonimmune hydrops fetalis diagnosed by exome sequencing.

To explain the importance of identifying an etiology for the pathological finding of nonimmune hydrops fetalis (NIHF) and to explore the impact of exome sequencing in recurrent NIHF. In addition, we present two cases of pregnancies affected with recurrent NIHF, in which genetic investigation was advantageous. Our study aimed to investigate the genetic background, if available, of all fetuses with NIHF referred to our tertiary medical center from January 2013 to August 2020. We summarized the etiology of NIHF if known, sonographic findings, genetic investigation and the pregnancies' outcomes. We encountered 144 families with NIHF. Genetic investigation was performed by chromosomal microarray analysis (CMA) in 63 (63/144. 44%) fetuses. Seventeen of 63 (27%) had a positive CMA result. In the negative CMA group, 15 (15/46, 33%) opted for exome sequencing, of which seven exomes were positive (47%). Among these, there were four couples with recurrent pregnancies affected by hydrops. Among the remaining 11 exome investigations for non-recurrent hydrops, another three were diagnostic. As identifying the etiology of the NIHF is an invaluable tool for the prognosis of the pregnancy, exome sequencing can provide further elucidation of the underlying pathogenesis of NIHF. Thus, genetic investigation should be recommended for cases of NIHF.

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

(N Engl J Med. 2020;383:1746–1756) Nonimmune hydrops fetalis (NIHF) is a severe disorder associated with a high risk of stillbirth, preterm birth, neonatal death, and neonatal complications. NIHF is a shared presentation of a number of genetic disorders. Using standard genetic testing with karyotyping or chromosomal microarray, the cause of NIHF can be determined in only 25% of cases. Single-gene disorders may substantially contribute to NIHF, but this is not yet clear. This study aimed to explore the use of exome sequencing for diagnosing single-gene disorders in unexplained NIHF cases and establish the diagnostic yield of exome sequencing.

Non-immunologic hydrops fetalis and coronavirus disease (COVID-19) – A case report

Non-immune hydrops fetalis is a severe fetal condition defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities. The prevalence of non-immune hydrops fetalis is unknown. Currently, about 90% of cases of hydrops fetalis are non-immune hydrops fetalis. Non-immune hydrops fetalis causes are multi-factorial. The pathophysiological mechanism of non-immunologic hydrops fetalis is related to abnormal fluid transportation between plasma and tissues. This is due to the increase in hydrostatic capillary pressure and capillary permeability and a reduction of the plasma osmotic pressure or lymphatic flow. A variety of viral infection agents have been associated with non-immune hydrops fetalis like parvovirus B19, herpes simplex virus, cytomegalovirus, Toxoplasma gondii, Treponema pallidum, but even other viruses that attack the maternal and fetus during pregnancy cannot be excluded as possible causes of non-immune hydrops fetalis. We present one case of non-immune hydrops fetalis who was diagnosed intra-uterine, three weeks after recovery from Coronavirus disease (COVID-19). After much investigation, we could not find any known factor that may be the cause of non-immunologic hydrops fetalis. Therefore, we predisposed a possible causal connection between nonimmunologic hydrops fetalis and Coronavirus disease (COVID-19).